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September 1992, Vol 49, No. 9 >
Article | September 1992

There Is More Than One Way to Collect Data for Linkage Analysis: Title and subTitle BreakWhat a Study of Epilepsy Can Tell Us About Linkage Strategy for Psychiatric Disease

David A. Greenberg, MD, PhD
[+] Author Affiliations

Accepted for publication April 2, 1992.

Reprint requests to Department of Psychiatry, Mount Sinai Medical Center, One Gustave L. Levy PI, New York, NY 10029-6574 (Dr Greenberg).


Arch Gen Psychiatry. 1992;49(9):745-750. doi:10.1001/archpsyc.1992.01820090073012
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• The most popular strategy for finding genes in psychiatric diseases has been to focus on large pedigrees with many affected members. While this strategy has sound advantages, it also has drawbacks that have seldom been addressed. The strategy of using smaller families also has its place in a linkage analysis. To illustrate the point, I discuss herein the successful search for a gene for another common complex disease, namely, idiopathic primary generalized epilepsy. There, investigators in the Los Angeles (Calif) Epilepsy Program used mostly nuclear families who were chosen through a proband with highly specific characteristics. An independent study, using a different strategy but one still focused on small families, then confirmed the linkage. However, investigators of both epilepsy projects put much care into determining which clinical characteristics would be used to define the index cases. The implications for the study of psychiatric disease are as follows: (1) careful attention must be paid to clinical presentation, and (2) there is room for both large-pedigree and smallfamily strategies in designing linkage studies.

REFERENCES

1 +
Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE, Watkins PC, Ottina K, Wallace MR, Sakaguchi AY, Young AB, Shoulson I, Bonilla E, Martin JB.  A polymorphic DNA marker genetically linked to Huntington's disease . Nature . 1983;;306:234.
2 +
Crow TJ.  Nature of the genetic contribution to psychotic illness: a continuum viewpoint . Acta Psychiatr Scand . 1990;;81:401-408.
3 +
Owen MJ, Lewis SW, Murray RM.  Family history and cerebral ventricular enlargement in schizophrenia: a case control study . Br J Psychiatry . 1989;;154:629-634.
4 +
Regier DA, Judd LL. Request for Applications . Rockville, Md: National Institute of Mental Health. Diagnostic Centers for Psychiatric Linkage Studies; 1989;.
5 +
Hodge SE.  Do bilineal pedigrees represent a problem for linkage analysis? Basic principles and simulation results for single-gene diseases with no heterogeneity . Genet Epidemiol . In press.
6 +
Spence MA, Bishop DT, Boehnke M, Elston RC, Falk C, Hodge SE, Ott J, Rice J, Merikangas K, Kupfer D. Methodological Issues in Linkage Analyses for Psychiatric Disorders: Secular Trends, Assortative Mating, Bilineal Pedigrees. Chicago, Ill: Task Force for the Development of Analytic Strategies for Linkage Studies of Psychiatric Disorders, John D. and Catherine T. MacArthur Foundation Research Network on the Psychobiology of Drepression and Other Affective Disorders; 1992. Internal Summary Report.
7 +
Leppert M, Anderson VE, Quattlebaum T, Stauffer D, O'Conner P, Makamura Y, Lalouel JM, White R.  Benign familial neonatal convulsions linked to genetic markers on chromosome 20 . Nature . 1989;;337:647-648.
8 +
Sander T, Durner M, Johnson K, Janz D.  Exclusion of linkage between the susceptibility locus for benign familial neonatal convulsions with idiopathic generalized epilepsies in juvenile myoclonic epilepsy families . Epilepsia . 1990;;31:815.
9 +
Greenberg DA, Delgado-Escueta AV, Widelitz H, Sparkes RS, Treiman L, Maldonado H, Terasaki PI, Park MS.  Juvenile myoclonic epilepsy (JME) may be linked to the BF and HLA loci on human chromosome 6 . Am J Med Genet . 1988;;31:185-192.
10 +
Greenberg DA, Delgado-Escueta AV, Widelitz H, Abad P, Park MS.  Strengthened evidence for linkage of juvenile myoclonic epilepsy to HLA and BF: human gene mapping 10 . Cytogenet Cell Genet . 1989;;51:1008.
11 +
Weissbecker K, Durner M, Scaramelli A, Janz D, Sparkes RS, Spence MA.  Confirmation of linkage between juvenile myoclonic epilepsy and the HLA region of chromosome 6 . Am J Med Genet . 1991;; 38:32-36.
12 +
Durner M, Sander T, Greenberg DA, Johnson K, Beck-Mannagetta G, Janz D.  Localization of idiopathic generalized epilepsy on chromosome 6p in the families of juvenile myoclonic epilepsy patients . Neurology . 1991;;41: 1651-1655.
13 +
McGue M, Gottesman II.  The genetic epidemiology of schizophrenia and the design of linkage studies . Eur Arch Psychiatry Clin Neurosci . 1991;; 240:174-181.
14 +
Egeland JA, Gerhard DS, Pauls DL, Sussex JN, Kidd KK, Allen CR, Hostetter AM, Housman DE.  Bipolar affective disorders linked to DNA markers on chromosome 11 . Nature . 1987;;325:783-787.
15 +
Kelsoe JR, Ginns El, Egeland JA, Gerhard DS, Goldstein AM, Bale SJ, Pauls DL, Long RT, Kidd KK, Conte G, Housman DE, Paul SM.  Re-evaluation of the linkage relationship between chromosome 11p loci and the gene for bipolar affective disorder in the Old Order Amish . Nature . 1989;;342:238-243.
16 +
Pauls DL.  The effect of changes in diagnosis on the evidence for genetic linkage . Psychiatr Genet . 1991;;2:3.
17 +
Hodge SE, Greenberg DA.  Sensitivity of lod scores to changes diagnostic status . Am J Hum Genet . 1992;;50:1053-1066.
18 +
Durner M, Greenberg DA, Hodge SE.  Inter- and intrafamilial heterogeneity: effective sampling strategies and comparison of methods . Am J Hum Genet . In press.
19 +
Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M.  Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene . Science . 1991;;252:704-706.
20 +
Ott J. Analysis of Human Genetic Linkage . Baltimore, Md: The Johns Hopkins University Press; 1991;:222-227.
21 +
Cavalli-Sforza LL, King MC.  Detecting linkage for genetically heterogeneous diseases and detecting heterogeneity with linkage data . Am J Hum Genet . 1986;;38:599-616.
22 +
Martinez MM, Goldin LR.  The detection of linkage and heterogeneity in nuclear families for complex disorders: one versus two marker loci . Am J Hum Genet . 1989;;44:552-559.
23 +
Greenberg DA.  Inferring mode of inheritance by comparison of lod scores . Am I Med Genet . 1989;;34:480-486.
24 +
Ewens WJ, Shute NCE.  A resolution of the ascertainment sampling problem, I: theory . Theor Popul Biol . 1986;;30:388-412.
25 +
Clerget-Darpoux F, Bonaiti-Pellie C, Hochez J.  Effects of misspecifying genetic parameters in lod score analysis . Biometrics . 1986;;42:393-399.
26 +
Elston RC.  Man bites dog? The validity of maximizing lod scores to determine mode of inheritance . Am J Med Genet . 1989;;34:487-488.
27 +
Durner M, Greenberg DA.  The effect of heterogeneity on linkage analysis . Am J Med Genet . 1992;;42:271-275.
28 +
Risch N.  A note on multiple testing procedures in linkage analysis . Am J Hum Genet . 1991;;48:1058-1064.
29 +
Lennox WG. Epilepsy and Related Disorders . Boston, Mass: Little Brown & Co Inc; 1960;:536-571.
30 +
Gedda L, Tatarelli R.  Essential isochronic epilepsy in MZ twin pairs . Acta Genet Med Gemellol . 1971;;20:380-383.
31 +
Berkovic FS, Howell RA, Hopper JL, Hay DA, Andermann E.  A twin study of the epilepsies . Epilepsia . 1990;;31:813.
32 +
Porter RJ. Epilepsy: 100 Elementary Principles . Philadelphia, Pa: WB Saunders Co; 1984;:29-42.
33 +
Janz D, Christian W.  Impulsiv-petit mal . D Zschr Nervenheilk . 1957;; 19:155-182.
34 +
Resor SR, Resor LD.  The neuropharmacology of juvenile myoclonic epilepsy . Clin Neuropharmacol . 1990;;13:465-491.
35 +
Delgado-Escueta A, Treiman DM, Enrile-Bacsal F.  Phenotypic variations of seizures in adolescents and adults . In: Anderson VE, Hauser WA, Penry JK, Sing CF, eds. Genetic Basis of the Epilepsies . New York, NY: Raven Press; 1982;:49-81.
36 +
Janz D.  Juvenile myoclonic epilepsy . Cleve Clin J Med . 1989;; 56( (suppl 1) ):23-33.
37 +
Tsuboi T, Christian W.  On the genetics of the primary generalized epilepsy with sporadic myoclonias of impulsive petit mal type: a clinical and electroencephalographic study of 399 probands . Humangenetik . 1973;;19: 155-182.
38 +
Holzman PS, Soloman CM, Levin S. Watermaux CS.  Pursuit eye movement dysfunctions in schizophrenia: family evidence for specificity . Arch Gen Psychiatry . 1984;;41:136-139.
39 +
Keefe RSE, Lobel DS, Mohs RC, Silverman JM, Harvey PD, Davidson M, Losonczy MF, Davis KL.  Diagnostic issues in chronic schizophrenia: kraepelinian schizophrenia, undifferentiated schizophrenia, and state-independent negative symptoms . Schizophr Res . 1991;;4:71-79.
40 +
Murray RM. The rediscovery and causes of dementia praecox. Presented at the 30th Meeting of the American College of Neuropsychopharmacology; December 11, 1991; San Juan, Puerto Rico.
41 +
Jones P, Murray RM.  The genetics of schizophrenia is the genetics of neurodevelopment . Br J Psychiatry . 1991;;158:615-623.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE, Watkins PC, Ottina K, Wallace MR, Sakaguchi AY, Young AB, Shoulson I, Bonilla E, Martin JB.  A polymorphic DNA marker genetically linked to Huntington's disease . Nature . 1983;;306:234.
2 +
Crow TJ.  Nature of the genetic contribution to psychotic illness: a continuum viewpoint . Acta Psychiatr Scand . 1990;;81:401-408.
3 +
Owen MJ, Lewis SW, Murray RM.  Family history and cerebral ventricular enlargement in schizophrenia: a case control study . Br J Psychiatry . 1989;;154:629-634.
4 +
Regier DA, Judd LL. Request for Applications . Rockville, Md: National Institute of Mental Health. Diagnostic Centers for Psychiatric Linkage Studies; 1989;.
5 +
Hodge SE.  Do bilineal pedigrees represent a problem for linkage analysis? Basic principles and simulation results for single-gene diseases with no heterogeneity . Genet Epidemiol . In press.
6 +
Spence MA, Bishop DT, Boehnke M, Elston RC, Falk C, Hodge SE, Ott J, Rice J, Merikangas K, Kupfer D. Methodological Issues in Linkage Analyses for Psychiatric Disorders: Secular Trends, Assortative Mating, Bilineal Pedigrees. Chicago, Ill: Task Force for the Development of Analytic Strategies for Linkage Studies of Psychiatric Disorders, John D. and Catherine T. MacArthur Foundation Research Network on the Psychobiology of Drepression and Other Affective Disorders; 1992. Internal Summary Report.
7 +
Leppert M, Anderson VE, Quattlebaum T, Stauffer D, O'Conner P, Makamura Y, Lalouel JM, White R.  Benign familial neonatal convulsions linked to genetic markers on chromosome 20 . Nature . 1989;;337:647-648.
8 +
Sander T, Durner M, Johnson K, Janz D.  Exclusion of linkage between the susceptibility locus for benign familial neonatal convulsions with idiopathic generalized epilepsies in juvenile myoclonic epilepsy families . Epilepsia . 1990;;31:815.
9 +
Greenberg DA, Delgado-Escueta AV, Widelitz H, Sparkes RS, Treiman L, Maldonado H, Terasaki PI, Park MS.  Juvenile myoclonic epilepsy (JME) may be linked to the BF and HLA loci on human chromosome 6 . Am J Med Genet . 1988;;31:185-192.
10 +
Greenberg DA, Delgado-Escueta AV, Widelitz H, Abad P, Park MS.  Strengthened evidence for linkage of juvenile myoclonic epilepsy to HLA and BF: human gene mapping 10 . Cytogenet Cell Genet . 1989;;51:1008.
11 +
Weissbecker K, Durner M, Scaramelli A, Janz D, Sparkes RS, Spence MA.  Confirmation of linkage between juvenile myoclonic epilepsy and the HLA region of chromosome 6 . Am J Med Genet . 1991;; 38:32-36.
12 +
Durner M, Sander T, Greenberg DA, Johnson K, Beck-Mannagetta G, Janz D.  Localization of idiopathic generalized epilepsy on chromosome 6p in the families of juvenile myoclonic epilepsy patients . Neurology . 1991;;41: 1651-1655.
13 +
McGue M, Gottesman II.  The genetic epidemiology of schizophrenia and the design of linkage studies . Eur Arch Psychiatry Clin Neurosci . 1991;; 240:174-181.
14 +
Egeland JA, Gerhard DS, Pauls DL, Sussex JN, Kidd KK, Allen CR, Hostetter AM, Housman DE.  Bipolar affective disorders linked to DNA markers on chromosome 11 . Nature . 1987;;325:783-787.
15 +
Kelsoe JR, Ginns El, Egeland JA, Gerhard DS, Goldstein AM, Bale SJ, Pauls DL, Long RT, Kidd KK, Conte G, Housman DE, Paul SM.  Re-evaluation of the linkage relationship between chromosome 11p loci and the gene for bipolar affective disorder in the Old Order Amish . Nature . 1989;;342:238-243.
16 +
Pauls DL.  The effect of changes in diagnosis on the evidence for genetic linkage . Psychiatr Genet . 1991;;2:3.
17 +
Hodge SE, Greenberg DA.  Sensitivity of lod scores to changes diagnostic status . Am J Hum Genet . 1992;;50:1053-1066.
18 +
Durner M, Greenberg DA, Hodge SE.  Inter- and intrafamilial heterogeneity: effective sampling strategies and comparison of methods . Am J Hum Genet . In press.
19 +
Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M.  Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene . Science . 1991;;252:704-706.
20 +
Ott J. Analysis of Human Genetic Linkage . Baltimore, Md: The Johns Hopkins University Press; 1991;:222-227.
21 +
Cavalli-Sforza LL, King MC.  Detecting linkage for genetically heterogeneous diseases and detecting heterogeneity with linkage data . Am J Hum Genet . 1986;;38:599-616.
22 +
Martinez MM, Goldin LR.  The detection of linkage and heterogeneity in nuclear families for complex disorders: one versus two marker loci . Am J Hum Genet . 1989;;44:552-559.
23 +
Greenberg DA.  Inferring mode of inheritance by comparison of lod scores . Am I Med Genet . 1989;;34:480-486.
24 +
Ewens WJ, Shute NCE.  A resolution of the ascertainment sampling problem, I: theory . Theor Popul Biol . 1986;;30:388-412.
25 +
Clerget-Darpoux F, Bonaiti-Pellie C, Hochez J.  Effects of misspecifying genetic parameters in lod score analysis . Biometrics . 1986;;42:393-399.
26 +
Elston RC.  Man bites dog? The validity of maximizing lod scores to determine mode of inheritance . Am J Med Genet . 1989;;34:487-488.
27 +
Durner M, Greenberg DA.  The effect of heterogeneity on linkage analysis . Am J Med Genet . 1992;;42:271-275.
28 +
Risch N.  A note on multiple testing procedures in linkage analysis . Am J Hum Genet . 1991;;48:1058-1064.
29 +
Lennox WG. Epilepsy and Related Disorders . Boston, Mass: Little Brown & Co Inc; 1960;:536-571.
30 +
Gedda L, Tatarelli R.  Essential isochronic epilepsy in MZ twin pairs . Acta Genet Med Gemellol . 1971;;20:380-383.
31 +
Berkovic FS, Howell RA, Hopper JL, Hay DA, Andermann E.  A twin study of the epilepsies . Epilepsia . 1990;;31:813.
32 +
Porter RJ. Epilepsy: 100 Elementary Principles . Philadelphia, Pa: WB Saunders Co; 1984;:29-42.
33 +
Janz D, Christian W.  Impulsiv-petit mal . D Zschr Nervenheilk . 1957;; 19:155-182.
34 +
Resor SR, Resor LD.  The neuropharmacology of juvenile myoclonic epilepsy . Clin Neuropharmacol . 1990;;13:465-491.
35 +
Delgado-Escueta A, Treiman DM, Enrile-Bacsal F.  Phenotypic variations of seizures in adolescents and adults . In: Anderson VE, Hauser WA, Penry JK, Sing CF, eds. Genetic Basis of the Epilepsies . New York, NY: Raven Press; 1982;:49-81.
36 +
Janz D.  Juvenile myoclonic epilepsy . Cleve Clin J Med . 1989;; 56( (suppl 1) ):23-33.
37 +
Tsuboi T, Christian W.  On the genetics of the primary generalized epilepsy with sporadic myoclonias of impulsive petit mal type: a clinical and electroencephalographic study of 399 probands . Humangenetik . 1973;;19: 155-182.
38 +
Holzman PS, Soloman CM, Levin S. Watermaux CS.  Pursuit eye movement dysfunctions in schizophrenia: family evidence for specificity . Arch Gen Psychiatry . 1984;;41:136-139.
39 +
Keefe RSE, Lobel DS, Mohs RC, Silverman JM, Harvey PD, Davidson M, Losonczy MF, Davis KL.  Diagnostic issues in chronic schizophrenia: kraepelinian schizophrenia, undifferentiated schizophrenia, and state-independent negative symptoms . Schizophr Res . 1991;;4:71-79.
40 +
Murray RM. The rediscovery and causes of dementia praecox. Presented at the 30th Meeting of the American College of Neuropsychopharmacology; December 11, 1991; San Juan, Puerto Rico.
41 +
Jones P, Murray RM.  The genetics of schizophrenia is the genetics of neurodevelopment . Br J Psychiatry . 1991;;158:615-623.

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